The present research program uses a "forward genetic approach" to define genes that determine cellular responses to nervous system injury. Of particular interest are the processes that lead either to secondary degeneration or cellular repair. In forward genetics, one screens for animals that carry genes that produce a particular phenotype, and then use these animals to define the genes and identify their mechanism of action. The present experiments are based upon the discovery of two dramatic phenotypes in mice in which there is a fundamentally different cellular response to nervous system injury. Specifically, certain inbred strains of mice do not show progressive degeneration following spinal cord injury, and instead exhibit a unique wound healing response. The same strains are invulnerable to certain types of excitatory amino acid neurotoxicity, including the neurotoxic cell death that occurs as a result of seizures. These two phenotypes may reflect the same cellular mechanism (invulnerability to EAA-induced cell death). There are 4 Specific Aims: 1) to determine the extent to which the wound healing response in the injured spinal cord creates an environment that is favorable to neuronal survival, axonal regeneration and functional recovery; 2) to determine whether invulnerability to EAA- induced neurotoxicity reduces the extent of secondary degeneration following spinal cord injury and stroke; 3) to define the cellular mechanisms that are responsible for the invulnerability to EAA-induced neurotoxicity; and 4) to identify the genetic basis of the invulnerability to EAA-induced neurotoxicity.